by Ingrid Fadelli, Medical Xpress
edited by Sadie Harley, reviewed by Robert Egan
Image illustrates that astrocyte reactivity associates with amyloid-β only when microglia are reactive. As shown, the brain surface on the left (microglia non-reactive group) appears blank, whereas the right panel (microglia reactive group) displays multiple significant blue regions, indicating this association. Credit: Ferrari-Souza, J.P., Povala, G., Rahmouni, N. et al. Microglia modulate Aβ-dependent astrocyte reactivity in Alzheimer’s disease. Nat Neurosci (2025). 10.1038/s41593-025-02103-0.
Alzheimer’s disease (AD) is a highly debilitating neurodegenerative disease characterized by the progressive loss of memory and decline of mental functions. Earlier research has uncovered some of the neural and biological underpinnings of AD, but many of the processes involved in its emergence remain poorly understood.
Well-documented features of AD include the presence of sticky protein clumps called amyloid-β (Aβ) plaques and of twisted proteins known as tau tangles inside neurons, as well as an increased reactivity of astrocytes. Astrocytes are brain cells that support the functioning of neurons, but that can prompt inflammation when reactive.
While past studies have linked these features to AD, the neurobiological processes that contribute to their emergence have not yet been clearly elucidated.
Researchers at Universidade Federal do Rio Grande Do Sul, McGill University, University of Pittsburgh and other institutes recently set out to explore the role of microglia, the primary immune cells in the human brain, in the reactivity of astrocytes, buildup of amyloid and the abnormal accumulation of tau protein.
Their paper, published in Nature Neuroscience, offers new valuable insight that could enrich the present understanding of AD. Specifically, the team gathered evidence suggesting that the activation of microglia amplifies the formation of Aβ plaques and the reactivity of astrocytes, which in turn induces the abnormal accumulation of tau and cognitive deterioration.
“The inspiration for our study came from the seminal work by Liddelow and Barres, which demonstrated that microglia can trigger astrocyte reactivity,” Eduardo R. Zimmer, co-senior author of the paper, told Medical Xpress.
“We designed a study to test whether this phenomenon could be observed in living individuals—and the answer appears to be yes.”
Investigating brain inflammation in AD
As part of their recent study, Zimmer and his colleagues studied more than 300 brains of individuals across the aging and AD spectrum, using positron emission tomography (PET). PET is an imaging technique that relies on a safe radioactive substance injected into the body to track the activity levels of cells in different regions.
Using this imaging method, along with other experimental tools, the researchers quantified Aβ plaques and tau tangles in the brains of the study participants, while also tracking the activation of microglia. To measure the reactivity of astrocytes, they also collected blood samples from the participants.
“We used state-of-the-art neuroimaging and ultrasensitive fluid biomarkers to assess the interplay between glial reactivity and AD hallmark proteins,” explained João Pedro Ferrari-Souza, first author of the study. “By integrating these tools with robust statistical modeling, we found that glial biomarker levels—and their interactions—provide valuable insights to better understand the multifaceted nature of AD.”
Implications for the understanding and treatment of AD
When they analyzed the data they collected, the researchers found that the presence of Aβ plaques was associated with astrocyte reactivity only when microglia were activated. Therefore, the activation of microglia appeared to modulate the harmful effects of Aβ on the reactivity of astrocytes, which further contributes to disease progression.
“The finding that astrocyte reactivity associates with amyloid-β only in the presence of microglial activation supports a model in which these cells dynamically interact during disease progression,” said Zimmer. “It suggests that this interplay positions both cell types as promising pharmacological targets.”
Overall, this study suggests that microglia play a crucial role in the neuroinflammatory process contributing to AD development. In the future, the team’s findings could inform the development of alternative treatments for AD aimed at slowing down its progression by lowering the activation of microglia.
Meanwhile, Zimmer and his colleagues plan to conduct additional mechanistic studies to better understand the role of microglia activation in AD. In addition, they hope to replicate their findings in more experiments that also involve underrepresented populations.
“We also want to study how the interplay between microglia and astrocytes could facilitate amyloid clearance in anti-amyloid therapies,” added Pedro Rosa-Neto, co-senior author of the paper.
Written for you by our author Ingrid Fadelli, edited by Sadie Harley, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You’ll get an ad-free account as a thank-you.
More information: João Pedro Ferrari-Souza et al, Microglia modulate Aβ-dependent astrocyte reactivity in Alzheimer’s disease, Nature Neuroscience (2025). DOI: 10.1038/s41593-025-02103-0.
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